The human T lymphotropic virus type I (HTLV-I) is associated with a chronic progressive myelopathy known as HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic progressive form of multiple sclerosis (MS). Other viruses such as human herpes virus type 6 (HHV-6) have also been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aid in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology. Areas of research addressing these neurovirological and neuroimmunological issues include: I) The host immune response to viruses from patients with HAM/TSP and MS with particular focus on virus-specific CD8+ cells and the definition of new viral epitopes recognized by these cells; II) The role of HHV-6 in the pathogenesis of MS and other chronic neurological disorders of the central nervous system; III) Immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are: 1) Increased HTLV-I specific CD8+ cells have been shown to be elevated in the peripheral blood and CSF of HAM/TSP patients and directly proportional to the amount of HTLV-I proviral DNA and RNA. Novel immunological methods for the detection of antigen-specific CD8+ cells have been developed based on the capacity of T cells to acquire MHC/peptide complexes. In this manner, new regions within the HTLV-I envelope gene have been defined that can serve as targets for HTLV-I specific T cells. In addition, the stage of maturation of these T cells has been analyzed with respect to phenotypic markers and function. Unlike CMV specific CTL which have a predominantly effector T cell phenotype, HTLV-I CD8+ T cells are memory cells which upon activation rapidly mature into effector cells. 2) We have completed recruitment of HAMTSP patients for a clinical trial of recombinant interferon b1a in HAM/TSP. We continue to support our preliminary results demonstrating a reduction in HTLV-I tax11-19 specific CD8+ T cells and HTLV-I induced spontaneous lymphoproliferation during and after treatment in the absence of a reduction in HTLV-I proviral load. We have actively pursued a detailed analysis of patients and controls with an HTLV-I seroindeterminate Western blot. We suggest that in some of these individuals, HTLV-I seroindeterminate Western blot reactivities represents exposure to prototype HTLV-I. We have begun a serum proteomic profiling analysis of patients with HAM/TSP, adult T cell leukemia, and controls. Unique ?signatures? have been demonstrated in patients with the identification of specific protein peaks that may be associated with an outcome of an HTLV-I infection. The application of this technology will be expanded to other neurologic diseases including MS. 3) HHV-6 continues to be detected in material from MS patients and has been specifically localized to MS plaques. Through laser assisted mirco-dissection techniques, autopsy material from brains of MS patients, patients with other diseases and normal control brains were analyzed for the presence of HHV-6 specific DNA sequences. Significant increases in the detection of HHV-6 was demonstrated in MS brains compared to controls. Cells phenotypically defined as astrocytes were shown to react with HHV-6 specific antibodies. Studies are currently underway to infect primary human glial cells with HHV-6. Both astrocytes and oligodendrocytes have been generated from human surgical biopsies and a systematic screening of this material for HHV-6 has been initiated. Preliminary results indicate the presence of HHV-6B specific DNA sequences in some brain biopsies in the absence of inflammation. Collectively, these results continue to define the role of human viruses that are associated with chronic progressive neurologic disease.